Interstitial Cystitis (IC), also known as Interstitial Cystitis/Bladder Pain Syndrome (IC/PBS) is a chronic, severely debilitating, painful condition due to inflammation of the tissues of the bladder wall. The cause is unknown. Symptoms include pelvic pain and pressure, urinary frequency, burning and urgency, and painful intercourse.
IC/BPS is frequently misdiagnosed as a urinary tract infection. Patients often go years without a correct diagnosis. On average, there is about a 4-year delay between the time the first symptoms occur and the diagnosis is made. The condition is usually diagnosed by ruling out other conditions (such as sexually transmitted disease, bladder cancer, and bladder infections). Testing for IC/BPS is not always reliable. The KCl test, also known as the potassium sensitivity test, uses a mild potassium solution to test the integrity of the bladder wall.
The condition generally occurs around age 30 to 50, although it has been reported in younger people. Women are 10 times more likely to have IC/BPS than men. Studies reveal that as many as 3 to 8 million Americans suffer from IC/BPS. The condition is associated with depression, emotional trauma, and other syndromes such as fibromyalgia, endometriosis, and irritable bowel syndrome. Advanced cases may reveal ulcers and erosions in the bladder lining with ultimate scarring and shrinkage of the bladder.
The cause of IC/BPS is unknown. Theories have included neurologic, allergic, autoimmune, toxic exposure, genetic, abnormal mast cells, and psychological. It appears that most patients suffer from a deficiency of the protective glycosaminoglycan (GAG) layer of the inner bladder lining (urothelium). This results in increased permeability of the underlying submucosal tissues with subsequent tissue destruction.
Other forms of cystitis are also known, including hemorrhagic cystitis (including radiation- and chemical-induced cystitis), traumatic cystitis, and chronic cystitis caused by an infectious agent. In each case, the condition is associated with inflammation of the urothelial lining and loss of the glycosaminoglycan (“GAG”) layer to some extent. This causes irritable voiding symptoms including pain, frequency, and urgency. Some of the most common forms of cystitis include:
Radiation Cystitis. This form of hemorrhagic cystitis can be disabling and potentially lethal. Radiation-induced degeneration and de-vascularization of the normal urothelium can occur even 10 years after ionizing radiation is delivered to the pelvis for the treatment of malignancy. Radiation cystitis can be treated with limited effectiveness and is usually incurable.
Chemical Cystitis. This form of hemorrhagic cystitis is often related to the administration of chemotherapy (cytoxan or ifosfamide). These agents can produce acrolein, which has an erosive effect on the urothelium and can cause significant irritative symptoms and even increase the risk for transitional cell carcinoma. Chemical cystitis can sometimes heal on its own.
Chronic Cystitis. Usually bacterial in origin (but can be viral), chronic cystitis is caused by infection. Bacterial infections make the bladder pre-disposed to recurrent infections and severe sensitivity with irritative symptoms. Symptoms can persist for some time even after the active infection is eradicated by appropriate antibiotic therapy.
There is no cure for interstitial cystitis, and there are no standard or consistently effective treatments. Treatment is currently based on trial and error and can include opioids, pain inhibitors, antidepressants, vistaril, detrussor relaxants, bladder hydrodistension, bladder instillations (in which a solution is introduced into the bladder via a catheter), biofeedback, dietary modification, and even surgery to enlarge or remove the bladder. Instillations are intravesical treatments typically performed with a number of different combination “cocktails” that may include dimethyl sulfoxide (DMSO), steroids, heparin, chlorpactin, lidocaine, sodium hyaluronate (cystistat), chondroitin (uracyst), and sodium bicarbonate.
Elmiron® (pentosan polysulfate) is the only medication taken by mouth that is specifically approved for treating IC. There have also been reported attempts in the literature at intravesical instillation of Elmiron®. The KCl test has been determined to be helpful in predicting the success of Elmiron®.
Pentosan polysulfate (also known as sodium pentosan polysulfate and pentosan polysulfate sodium) is related to the low molecular weight heparin class of molecules. The official Elmiron® website (www.orthoelmiron.com) states that it is not known exactly how Elmiron® works. Preliminary clinical models suggest that the medicine coats the bladder and the pentosan polysulfate repairs damaged glycosaminoglycan (GAG) layers lining the urothelium. In vitro data suggest that it may provide an anti-inflammatory effect in patients with IC. Pentosan polysulfate shows beneficial effects in a proportion of patients with IC in terms of the improvement of a patient's overall condition and the relief of pain, and it is a generally well tolerated therapy. (Pentosan polysulfate: a review of its use in the relief of bladder pain or discomfort in interstitial cystitis. Anderson V R, Perry C M, Drugs. 2006; 66(6):821-35.) Although most controlled trials suggest a positive effect of oral Elmiron®, some studies have shown little benefit over placebo. It is the only U.S. FDA-approved oral treatment for the relief of bladder pain or discomfort associated with IC. The usual dose is 100 mg taken before or after meals three times per day. A veterinary version of Elmiron® is available under the trademark Cartrophen Vet®.
When administered orally, Elmiron® has pharmacokinetic limitations, as only 6% is absorbed and reaches the circulation, and a mean of 6% of an oral dose is excreted in the urine, mostly as desulfated and depolymerized metabolites. Only a small fraction of the administered dose (mean 0.14%) is recovered as intact drug in urine.
Oral Elmiron® is also associated with several systemic side effects, including hair loss, GI intolerance, headache, rash, sleep disturbance, and vertigo. Rarely, blood thinning can result.
Dr Lowell Parsons, who conducted the original studies on Elmiron®, has also studied intravesical Elmiron® instillation. According to the IC network, an online site that provides information about interstitial cystitis, several preliminary research studies that discussed new instillations were presented at the Bladder Symposium in October 2003, including: #1. Lowell Parsons presented the results for using Elmiron® intravesically. 40 patients were evaluated. 20 received heparin only (40,000 units of heparin) and 20 received Elmiron® (a solution of 100 mg oral Elmiron, 80 mg lidocaine and 3 cc's of sodium bicarb). 31 subjects had significant symptom relief. Nine had no change in their symptoms. In response to therapy, there was no significant difference between the two solutions. While heparin and Elmiron® had equal efficacy in the intravesical therapeutic solution, an advantage of pentosan polysulfate over heparin is its substantially lower cost.
There have been several reports in the literature describing the use of liposomes to coat the bladder. See, for example, Tyagi, P., et al., LUTS (2009) 1, S90-S93 (proposing that empty liposomes have a therapeutic effect by forming a coat on the injured urothelium and blocking irritation of submucosal afferent nerves); Lee, W. C., Kaohsiung J Med Sci 2011 Oct. 27 (10): 437-40 (reporting on the safety and dose flexibility clinical evaluation of liposomes in patients with IC, and documenting improvement in symptom scores and side effects); and Tyagi and Chancellor, BJU Int. 2009 December; 104(11):1689-92 (Epub 2009 Jul. 7) (comparing results in rats treated with instillation of liposomes versus intravesical pentosan polysulfate and versus intravesical DMSO. Intravesical liposomes had the most efficacy). Dr. Chancellor and the Lipella Company (www.lipella.com) have described the use of intravesical liposomes to carry the Botulinum toxin into the bladder wall.
Y C Chung et al. in J Urol 2009 October; 182(4):1393-400 reported on intravesical liposomes versus oral pentosan polysulfate for IC. They found intravesical liposomes achieved efficacy similar to that of oral pentosan polysulfate sodium, and concluded that intravesical liposomes appear to be a promising new treatment for interstitial cystitis/painful bladder syndrome. Some investigators have used empty liposomes to manage IC symptoms and found better results than with instillation of Elmiron® or DMSO. Tyagi P, Hsieh V C, Yoshimura N, Kaufman J, Chancellor M B, “Instillation of liposomes vs dimethyl sulphoxide or pentosan polysulphate for reducing bladder hyperactivity,” British Journal of Urology (BJU Int.) 2009 December; 104(11):1689-92. Epub 2009 Jul. 7. Y C Chung used empty liposomes and proved superior efficacy to oral Elmiron®. Chuang Y C, Lee W C, Lee W C, Chiang P H., J Urol. 2009 Aug. 13. Epub ahead of print. doi:10.1016/j.juro.2009.06.024.
Despite substantial efforts by the medical community to treat IC and other forms of cystitis, a truly effective treatment with few side effects has remained elusive.